Anaesthetic management of people with multiple sclerosis.

There is a lack of published guidelines on the management of patients with multiple sclerosis (MS) undergoing procedures that require anaesthesia and respective advice is largely based on retrospective studies or case reports. The aim of this paper is to provide recommendations for anaesthetists and neurologists for the management of patients with MS requiring anaesthesia. This review covers issues related to the anaesthetic management of patients with MS, with a focus on preoperative assessment, choice of anaesthetic techniques and agents, side-effects of drugs used during anaesthesia and their potential impact on the disease evolution, drug interactions that may occur, and the need to use monitoring devices. A systematic PubMed research was performed to retrieve relevant articles

Phase transition and correlation decay in Coupled Map Lattices

For a Coupled Map Lattice with a specific strong coupling emulating Stavskaya's probabilistic cellular automata, we prove the existence of a phase transition using a Peierls argument, and exponential convergence to the invariant measures for a wide class of initial states using a technique of decoupling originally developed for weak coupling. This implies the exponential decay, in space and in time, of the correlation functions of the invariant measures

On the basic computational structure of gene regulatory networks

Gene regulatory networks constitute the first layer of the cellular computation for cell adaptation and surveillance. In these webs, a set of causal relations is built up from thousands of interactions between transcription factors and their target genes. The large size of these webs and their entangled nature make difficult to achieve a global view of their internal organisation. Here, this problem has been addressed through a comparative study for {\em Escherichia coli}, {\em Bacillus subtilis} and {\em Saccharomyces cerevisiae} gene regulatory networks. We extract the minimal core of causal relations, uncovering the hierarchical and modular organisation from a novel dynamical/causal perspective. Our results reveal a marked top-down hierarchy containing several small dynamical modules for \textit{E. coli} and \textit{B. subtilis}. Conversely, the yeast network displays a single but large dynamical module in the middle of a bow-tie structure. We found that these dynamical modules capture the relevant wiring among both common and organism-specific biological functions such as transcription initiation, metabolic control, signal transduction, response to stress, sporulation and cell cycle. Functional and topological results suggest that two fundamentally different forms of logic organisation may have evolved in bacteria and yeast.Comment: This article is published at Molecular Biosystems, Please cite as: Carlos Rodriguez-Caso, Bernat Corominas-Murtra and Ricard V. Sole. Mol. BioSyst., 2009, 5 pp 1617--171

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

DNA replication stress is a source of genomic instability. Here we identify ​changed mutation rate 1 (​Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that ​Cmr1—together with ​Mrc1/​Claspin, ​Pph3, the chaperonin containing ​TCP1 (CCT) and 25 other proteins—define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to ​Cmr1, its human orthologue ​WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that ​Cmr1/​WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins

The MCM-Binding Protein ETG1 Aids Sister Chromatid Cohesion Required for Postreplicative Homologous Recombination Repair

The DNA replication process represents a source of DNA stress that causes potentially spontaneous genome damage. This effect might be strengthened by mutations in crucial replication factors, requiring the activation of DNA damage checkpoints to enable DNA repair before anaphase onset. Here, we demonstrate that depletion of the evolutionarily conserved minichromosome maintenance helicase-binding protein ETG1 of Arabidopsis thaliana resulted in a stringent late G2 cell cycle arrest. This arrest correlated with a partial loss of sister chromatid cohesion. The lack-of-cohesion phenotype was intensified in plants without functional CTF18, a replication fork factor needed for cohesion establishment. The synergistic effect of the etg1 and ctf18 mutants on sister chromatid cohesion strengthened the impact on plant growth of the replication stress caused by ETG1 deficiency because of inefficient DNA repair. We conclude that the ETG1 replication factor is required for efficient cohesion and that cohesion establishment is essential for proper development of plants suffering from endogenous DNA stress. Cohesion defects observed upon knockdown of its human counterpart suggest an equally important developmental role for the orthologous mammalian ETG1 protein

Elucidation of the Mode of Action of a New Antibacterial Compound Active against Staphylococcus aureus and Pseudomonas aeruginosa.

Nosocomial and community-acquired infections caused by multidrug resistant bacteria represent a major human health problem. Thus, there is an urgent need for the development of antibiotics with new modes of action. In this study, we investigated the antibacterial characteristics and mode of action of a new antimicrobial compound, SPI031 (N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol), which was previously identified in our group. This compound exhibits broad-spectrum antibacterial activity, including activity against the human pathogens Staphylococcus aureus and Pseudomonas aeruginosa. We found that SPI031 has rapid bactericidal activity (7-log reduction within 30 min at 4x MIC) and that the frequency of resistance development against SPI031 is low. To elucidate the mode of action of SPI031, we performed a macromolecular synthesis assay, which showed that SPI031 causes non-specific inhibition of macromolecular biosynthesis pathways. Liposome leakage and membrane permeability studies revealed that SPI031 rapidly exerts membrane damage, which is likely the primary cause of its antibacterial activity. These findings were supported by a mutational analysis of SPI031-resistant mutants, a transcriptome analysis and the identification of transposon mutants with altered sensitivity to the compound. In conclusion, our results show that SPI031 exerts its antimicrobial activity by causing membrane damage, making it an interesting starting point for the development of new antibacterial therapies

Alternative splicing enriched cDNA libraries identify breast cancer-associated transcripts

<p>Abstract</p> <p>Background</p> <p>Alternative splicing (AS) is a central mechanism in the generation of genomic complexity and is a major contributor to transcriptome and proteome diversity. Alterations of the splicing process can lead to deregulation of crucial cellular processes and have been associated with a large spectrum of human diseases. Cancer-associated transcripts are potential molecular markers and may contribute to the development of more accurate diagnostic and prognostic methods and also serve as therapeutic targets. Alternative splicing-enriched cDNA libraries have been used to explore the variability generated by alternative splicing. In this study, by combining the use of trapping heteroduplexes and RNA amplification, we developed a powerful approach that enables transcriptome-wide exploration of the AS repertoire for identifying AS variants associated with breast tumor cells modulated by <it>ERBB2</it> (<it>HER-2/neu</it>) oncogene expression.</p> <p>Results</p> <p>The human breast cell line (C5.2) and a pool of 5 ERBB2 over-expressing breast tumor samples were used independently for the construction of two AS-enriched libraries. In total, 2,048 partial cDNA sequences were obtained, revealing 214 alternative splicing sequence-enriched tags (ASSETs). A subset with 79 multiple exon ASSETs was compared to public databases and reported 138 different AS events. A high success rate of RT-PCR validation (94.5%) was obtained, and 2 novel AS events were identified. The influence of <it>ERBB2</it>-mediated expression on AS regulation was evaluated by capillary electrophoresis and probe-ligation approaches in two mammary cell lines (Hb4a and C5.2) expressing different levels of <it>ERBB2</it>. The relative expression balance between AS variants from 3 genes was differentially modulated by <it>ERBB2</it> in this model system.</p> <p>Conclusions</p> <p>In this study, we presented a method for exploring AS from any RNA source in a transcriptome-wide format, which can be directly easily adapted to next generation sequencers. We identified AS transcripts that were differently modulated by <it>ERBB2</it>-mediated expression and that can be tested as molecular markers for breast cancer. Such a methodology will be useful for completely deciphering the cancer cell transcriptome diversity resulting from AS and for finding more precise molecular markers.</p

The evolutionary significance of polyploidy

Polyploidy, or the duplication of entire genomes, has been observed in prokaryotic and eukaryotic organisms, and in somatic and germ cells. The consequences of polyploidization are complex and variable, and they differ greatly between systems (clonal or non-clonal) and species, but the process has often been considered to be an evolutionary 'dead end'. Here, we review the accumulating evidence that correlates polyploidization with environmental change or stress, and that has led to an increased recognition of its short-term adaptive potential. In addition, we discuss how, once polyploidy has been established, the unique retention profile of duplicated genes following whole-genome duplication might explain key longer-term evolutionary transitions and a general increase in biological complexity

Differences in the Number of Intrinsically Disordered Regions between Yeast Duplicated Proteins, and Their Relationship with Functional Divergence

BACKGROUND: Intrinsically disordered regions are enriched in short interaction motifs that play a critical role in many protein-protein interactions. Since new short interaction motifs may easily evolve, they have the potential to rapidly change protein interactions and cellular signaling. In this work we examined the dynamics of gain and loss of intrinsically disordered regions in duplicated proteins to inspect if changes after genome duplication can create functional divergence. For this purpose we used Saccharomyces cerevisiae and the outgroup species Lachancea kluyveri. PRINCIPAL FINDINGS: We find that genes duplicated as part of a genome duplication (ohnologs) are significantly more intrinsically disordered than singletons (p<2.2(e)-16, Wilcoxon), reflecting a preference for retaining intrinsically disordered proteins in duplicate. In addition, there have been marked changes in the extent of intrinsic disorder following duplication. A large number of duplicated genes have more intrinsic disorder than their L. kluyveri ortholog (29% for duplicates versus 25% for singletons) and an even greater number have less intrinsic disorder than the L. kluyveri ortholog (37% for duplicates versus 25% for singletons). Finally, we show that the number of physical interactions is significantly greater in the more intrinsically disordered ohnolog of a pair (p = 0.003, Wilcoxon). CONCLUSION: This work shows that intrinsic disorder gain and loss in a protein is a mechanism by which a genome can also diverge and innovate. The higher number of interactors for proteins that have gained intrinsic disorder compared with their duplicates may reflect the acquisition of new interaction partners or new functional roles

Quantitative Proteomic and Interaction Network Analysis of Cisplatin Resistance in HeLa Cells

Cisplatin along with other platinum based drugs are some of the most widely used chemotherapeutic agents. However drug resistance is a major problem for the successful chemotherapeutic treatment of cancer. Current evidence suggests that drug resistance is a multifactorial problem due to changes in the expression levels and activity of a wide number of proteins. A majority of the studies to date have quantified mRNA levels between drug resistant and drug sensitive cell lines. Unfortunately mRNA levels do not always correlate with protein expression levels due to post-transcriptional changes in protein abundance. Therefore global quantitative proteomics screens are needed to identify the protein targets that are differentially expressed in drug resistant cell lines. Here we employ a quantitative proteomics technique using stable isotope labeling with amino acids in cell culture (SILAC) coupled with mass spectrometry to quantify changes in protein levels between cisplatin resistant (HeLa/CDDP) and sensitive HeLa cells in an unbiased fashion. A total of 856 proteins were identified and quantified, with 374 displaying significantly altered expression levels between the cell lines. Expression level data was then integrated with a network of protein-protein interactions, and biological pathways to obtain a systems level view of proteome changes which occur with cisplatin resistance. Several of these proteins have been previously implicated in resistance towards platinum-based and other drugs, while many represent new potential markers or therapeutic targets